Breakthrough Flu Drug Might Already Exist

Breakthrough Flu Drug Might Already Exist

Structurally sound: The neuraminidase protein of the H1N1 virus is particularly adept at mutating to avoid attack. In this crystal structure, the mutations that allow it to resist Tamiflu and other antiviral drugs are visible as multicolored stick structures.

The flu virus is a wily target, constantly mutating to avoid attack from the immune system and from antiviral drugs like Tamiflu. But in research presented Sunday at the annual meeting of the American Society for Cell Biology (ASCB) in San Diego, scientists announced a new method for fighting pandemic influenzas such as H1N1 (swine) and H5N1 (avian).

The approach involves using massive amount of computer power to simulate never-before-seen conformations of a virus. Using the method, researchers at the University of California at San Diego have not only identified a new molecular target for influenza drugs, they have also found drugs already approved by the U.S. Food and Drug Administration that just might hit the target perfectly.

The target in question is a single, large protein called neuraminidase–one of two major proteins present on the surface of the influenza virus–that allows newly replicated viruses to be released into their host. Because most pandemic versions share the same neuraminidase subtype, N1, the protein is an ideal drug target.

Most molecular imaging or modeling focuses on determining the arrangement of atoms in a molecule’s crystal structure–a lengthy, energy-intensive process that provides a precise way to capture the molecule’s shape but only in one conformation, frozen at a single moment in time. In contrast, the new “relaxed complex” method models the virus protein molecule in a state that provides a better understanding of how the protein behaves and even revealing conformations that rarely occur.

Biochemist Andrew McCammon and undergraduate lab member Daniel Dadon used a sophisticated computer program to simulate all possible conformations–27 in all–of the H1N1 virus’s flexible neuraminidase protein. Rather than forcing the protein into a single crystal structure’s conformation, “[we] got a movie of how the protein would behave in nature,” Dadon says. “It’s like frames from a film, rather than a single photograph.”

Dadon aligned each of those 27 neuraminidase conformations and found that all of them had a binding site that remained unchanged, a single spot that could act as a prime inhibitor target. The researchers then looked at a library of drugs already approved by the FDA. After breaking molecular models of the drugs down into small fragments, they ran them through a colossal search algorithm in order to find those molecules with the highest affinity for the neuraminidase binding site.